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• W2807811455 abstract "The preimplantation mouse embryo is a simple self-contained system, making it an excellent model to discover how mammalian cells function in real time and in vivo. Work over the last decade has revealed some key morphogenetic mechanisms that drive early development, yielding rudimentary instructions for the generation of a mammalian embryo. Here, we review the instructions revealed thus far, and then discuss remaining challenges to discover upstream factors controlling cell fate determination, test the role of mechanisms based on biological noise, and take advantage of recent technological developments to advance the spatial and temporal resolution of our current understanding. The preimplantation mouse embryo is a simple self-contained system, making it an excellent model to discover how mammalian cells function in real time and in vivo. Work over the last decade has revealed some key morphogenetic mechanisms that drive early development, yielding rudimentary instructions for the generation of a mammalian embryo. Here, we review the instructions revealed thus far, and then discuss remaining challenges to discover upstream factors controlling cell fate determination, test the role of mechanisms based on biological noise, and take advantage of recent technological developments to advance the spatial and temporal resolution of our current understanding. A central question in developmental biology is how complex forms and functions arise from the simple starting point of a single cell. During morphogenesis, spatiotemporal order and patterning spontaneously emerge through local interactions at cellular and subcellular scales (Davies, 2017Davies J.A. Adaptive self-organization in the embryo: its importance to adult anatomy and to tissue engineering.J. Anat. 2017; 232: 524-533Crossref PubMed Scopus (0) Google Scholar, Sasai, 2013Sasai Y. Cytosystems dynamics in self-organization of tissue architecture.Nature. 2013; 493: 318-326Crossref PubMed Scopus (216) Google Scholar). This process of self-organization occurs in the absence of external control and results in the emergence of higher order properties that cannot be accounted for by the properties of the individual components. In this way, large numbers of cells can organize into complex tissues by obeying simple rules of local interaction without reference to a global pattern. Such self-organization has the advantage that it is relatively robust to error, highly scalable, and retains the capacity for self-repair. The preimplantation mouse embryo is an excellent system for studying how simple cells organize dynamically into increasingly complex structures. The mouse embryo executes a developmental program from zygote to hatched blastocyst without the requirement for external input and both cellular and subcellular elements of the embryo interact dynamically to generate emergent patterned structures. These elements consist of physical properties such as cell shape, adhesion and polarity, biochemical signaling and feedback loops, genetically encoded information, and stochastically generated variation (Nissen et al., 2017Nissen S.B. Perera M. Gonzalez J.M. Morgani S.M. Jensen M.H. Sneppen K. Brickman J.M. Trusina A. Four simple rules that are sufficient to generate the mammalian blastocyst.PLoS Biol. 2017; 15: e2000737Crossref PubMed Scopus (15) Google Scholar, White et al., 2016cWhite M.D. Zenker J. Bissiere S. Plachta N. How cells change shape and position in the early mammalian embryo.Curr. Opin. Cell Biol. 2016; 44: 7-13Crossref PubMed Scopus (2) Google Scholar, Wennekamp et al., 2013Wennekamp S. Mesecke S. Nedelec F. Hiiragi T. A self-organization framework for symmetry breaking in the mammalian embryo.Nat. Rev. Mol. Cell Biol. 2013; 14: 454-461Crossref Scopus (70) Google Scholar). Adaptive self-organization in response to the changing interactions between these elements enables robust regulative development of the embryo without the external imposition of order. In this way, the embryo progresses from a single cell into a complex multi-layered structure consisting of multiple cell lineages prior to implantation. In practical terms, the preimplantation mouse embryo represents an excellent midway point between complex tissues and organs, and simplistic cell culture systems (Figure 1). Progression through the entire preimplantation stage can proceed in vitro, in the absence of maternal tissues, without any discernible consequences on subsequent development (Whitten and Biggers, 1968Whitten W.K. Biggers J.D. Complete development in vitro of the pre-implantation stages of the mouse in a simple chemically defined medium.J. Reprod. Fertil. 1968; 17: 399-401Crossref PubMed Google Scholar). Even before fertilization, the mouse egg can be isolated and studied directly under the microscope, making it possible to dissect mechanisms of mammalian meiosis. When isolated after fertilization, the one-cell embryo undergoes cleavage divisions and develops as a self-contained group of blastomeres enclosed by the zona pellucida (ZP) and independent of interactions with extracellular matrices or tissues. This developing embryo can be imaged in such ex utero conditions until the blastocyst stage when it is ready for implantation into the uterus (Behringer, 2014Behringer R. Manipulating the Mouse Embryo: A Laboratory Manual. Cold Spring Harbor Laboratory Press, 2014Google Scholar, Brinster, 1963Brinster R.L. A method for in vitro cultivation of mouse ova from two-cell to blastocyst.Exp. Cell Res. 1963; 32: 205-208Crossref PubMed Google Scholar). The accessibility of the cultured mouse embryo to imaging and genetic manipulations while retaining the advantage of a physiological in vivo system has placed this system at the center of research in mammalian genetics, physiology, and development. Although there is some variability in timing, the major events of preimplantation development are well conserved across mammalian species (Reijo Pera and Prezzoto, 2016Reijo Pera R.A. Prezzoto L. Species-specific variation among mammals.Curr. Top. Dev. Biol. 2016; 120: 401-420Crossref PubMed Scopus (0) Google Scholar). From mouse to human, most mammals follow a general sequence of events consisting of fertilization followed by early development without embryonic transcription; cleavage divisions in the absence of growth; compaction to form a morula; and, finally, generation of a blastocyst. Early studies manipulating cells of the mouse embryo demonstrated that this developmental program is not predetermined, as in the case of lower organisms such as Drosophila, Caenorhabditis elegans, and Xenopus, but consists of varying division patterns and flexibility of cell fate that can compensate for cell loss (Hoppe and Whitten, 1972Hoppe P.C. Whitten W.K. Does X chromosome inactivation occur during mitosis of first cleavage?.Nature. 1972; 239: 520Crossref PubMed Scopus (15) Google Scholar, Tarkowski and Wroblewska, 1967Tarkowski A.K. Wroblewska J. Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage.J. Embryol. Exp. Morphol. 1967; 18: 155-180PubMed Google Scholar, Tarkowski, 1959Tarkowski A.K. Experiments on the development of isolated blastomeres of mouse eggs.Nature. 1959; 184: 1286-1287Crossref PubMed Scopus (0) Google Scholar) and even artificial rearrangements (Ziomek and Johnson, 1982Ziomek C.A. Johnson M.H. The roles of phenotype and position in guiding the fate of 16-cell mouse blastomeres.Dev. Biol. 1982; 91: 440-447Crossref PubMed Google Scholar, Ziomek et al., 1982Ziomek C.A. Johnson M.H. Handyside A.H. The developmental potential of mouse 16-cell blastomeres.J. Exp. Zool. 1982; 221: 345-355Crossref PubMed Google Scholar). These initial findings hinted at what is now thought to be a complex interaction of regulatory mechanisms working in concert to gradually drive cells toward separate fates. Intrinsic to this regulative process are not only subcellular processes but also intercellular interactions that lead to a progressive refinement of cellular identity. This plasticity, and the consequent ability to compensate in the face of internal or external disturbances, may be especially important in the context of mammalian development where significant energy and resources are invested into each embryo. Recent advances in live-cell imaging, computational cell tracking, and optogenetics are beginning to yield the details underlying these regulatory mechanisms and reveal how cells interact with their neighbors to resolve their fates within the intact developing embryo. Although some of the elements driving the self-organization of the preimplantation embryo have been identified, extensive work is still required to understand how multiple mechanisms operating at the level of the cell nucleus, cytoskeleton, and cell-cell interactions are integrated to fully assemble the embryo. The transformation from an egg to an embryo requires precise coordination of a series of intricate processes that unite the haploid genomes of each parent into a single diploid genome of a new living organism. However, preparation for these events begins long before fertilization with the maturation of the egg precursor cell, or oocyte (Figure 2). Within the ovary, oocytes are stored in a quiescent state, arrested in prophase of the first meiotic division. Surrounding support cells provide the oocyte with maternal mRNAs and proteins that will be required to sustain development through the first stages of life (Li and Albertini, 2013Li R. Albertini D.F. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte.Nat. Rev. Mol. Cell Biol. 2013; 14: 141-152Crossref PubMed Scopus (204) Google Scholar). In response to a surge of luteinizing hormone released from the pituitary gland, the oocyte resumes meiosis, breaks down its nucleus, and assembles a microtubule spindle around its chromosomes (Bury et al., 2017Bury L. Coelho P.A. Simeone A. Ferries S. Eyers C.E. Eyers P.A. Zernicka-Goetz M. Glover D.M. Plk4 and Aurora A cooperate in the initiation of acentriolar spindle assembly in mammalian oocytes.J. Cell Biol. 2017; 216: 3571-3590Crossref PubMed Scopus (3) Google Scholar). In a critical first step of symmetry breaking, the cortex of the oocyte softens and thickens, promoting migration of the spindle toward the nearest cortex (Chaigne et al., 2013Chaigne A. Campillo C. Gov N.S. Voituriez R. Azoury J. Umana-Diaz C. Almonacid M. Queguiner I. Nassoy P. Sykes C. et al.A soft cortex is essential for asymmetric spindle positioning in mouse oocytes.Nat. Cell Biol. 2013; 15: 958-966Crossref PubMed Scopus (64) Google Scholar). This off-center positioning of the spindle ensures the asymmetry of the first meiotic division. Unlike spindle positioning in somatic cells, which typically depends on astral microtubules, oocytes lack centrosomes, and therefore migration of the meiotic spindle is driven by actin polymerization (Yi et al., 2013Yi K. Rubinstein B. Unruh J.R. Guo F. Slaughter B.D. Li R. Sequential actin-based pushing forces drive meiosis I chromosome migration and symmetry breaking in oocytes.J. Cell Biol. 2013; 200: 567-576Crossref PubMed Scopus (60) Google Scholar, Dumont et al., 2007Dumont J. Million K. Sunderland K. Rassinier P. Lim H. Leader B. Verlhac M.H. Formin-2 is required for spindle migration and for the late steps of cytokinesis in mouse oocytes.Dev. Biol. 2007; 301: 254-265Crossref PubMed Scopus (132) Google Scholar). After spindle migration, the close proximity of the chromosomes to the cortex induces the formation of a cortical actomyosin cap (Deng et al., 2007Deng M. Suraneni P. Schultz R.M. Li R. The Ran GTPase mediates chromatin signaling to control cortical polarity during polar body extrusion in mouse oocytes.Dev. Cell. 2007; 12: 301-308Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). An actin flow is established that drives cytoplasmic streaming to maintain spindle positioning and the first polarization events (Yi et al., 2011Yi K. Unruh J.R. Deng M. Slaughter B.D. Rubinstein B. Li R. Dynamic maintenance of asymmetric meiotic spindle position through Arp2/3-complex-driven cytoplasmic streaming in mouse oocytes.Nat. Cell Biol. 2011; 13: 1252-1258Crossref PubMed Scopus (160) Google Scholar). The oocyte then undergoes a division that is extremely asymmetric in size and discards half of its chromosomes into a small cell, called the polar body, which will later degenerate. Recent high-resolution imaging studies have revealed that actin filaments also infiltrate the meiotic spindle and are crucial for correct alignment and segregation of the chromosomes (Mogessie and Schuh, 2017Mogessie B. Schuh M. Actin protects mammalian eggs against chromosome segregation errors.Science. 2017; 357https://doi.org/10.1126/science.aal1647Crossref PubMed Scopus (36) Google Scholar). Immediately after this division, the meiosis II spindle assembles around the chromosomes just under the cortex and the oocyte remains arrested at this stage, awaiting fertilization. Completion of the maturation process can occur spontaneously in isolated oocytes in vitro (Edwards, 1965Edwards R.G. Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes.Nature. 1965; 208: 349-351Crossref PubMed Scopus (574) Google Scholar), indicating that it proceeds by self-organization. Fusion of a sperm with the mature oocyte triggers the completion of meiosis II with another asymmetric division that generates a second polar body, translation of maternal mRNAs, and the progression from meiosis to mitosis (Clift and Schuh, 2013Clift D. Schuh M. Restarting life: fertilization and the transition from meiosis to mitosis.Nat. Rev. Mol. Cell Biol. 2013; 14: 549-562Crossref PubMed Scopus (118) Google Scholar). The first mitotic division in the newly formed zygote is also dependent on actin networks (Chaigne et al., 2016Chaigne A. Campillo C. Voituriez R. Gov N.S. Sykes C. Verlhac M.H. Terret M.E. F-actin mechanics control spindle centring in the mouse zygote.Nat. Commun. 2016; 7: 10253Crossref PubMed Scopus (33) Google Scholar). However unlike in the oocyte, the zygotic spindle is positioned centrally and the subsequent division is symmetric, thereby producing two daughter cells, or blastomeres, of similar sizes. Thus, the transition from meiosis to mitosis is complete (Figure 2). Upon fertilization, the maternal chromosomes and the sperm chromatin decondense and form separate pronuclei. Within each pronucleus there is a distinct program of epigenetic remodeling of the parental DNA to remove gamete-specific modifications and transform the zygote to a totipotent state. Changes in DNA methylation, histone modifications, and activation of retrotransposons all contribute to nuclear remodeling (Habibi and Stunnenberg, 2017Habibi E. Stunnenberg H.G. Transcriptional and epigenetic control in mouse pluripotency: lessons from in vivo and in vitro studies.Curr. Opin. Genet. Dev. 2017; 46: 114-122Crossref PubMed Scopus (6) Google Scholar, Jachowicz et al., 2017Jachowicz J.W. Bing X. Pontabry J. Boskovic A. Rando O.J. Torres-Padilla M.E. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo.Nat. Genet. 2017; 49: 1502-1510Crossref PubMed Scopus (46) Google Scholar, Burton and Torres-Padilla, 2014Burton A. Torres-Padilla M.E. Chromatin dynamics in the regulation of cell fate allocation during early embryogenesis.Nat. Rev. Mol. Cell Biol. 2014; 15: 723-734Crossref PubMed Scopus (91) Google Scholar). It has been proposed that differences between cells of the embryo do not arise until the 16-cell stage when the cells first adopt inner and outer positions (Alarcon and Marikawa, 2005Alarcon V.B. Marikawa Y. Unbiased contribution of the first two blastomeres to mouse blastocyst development.Mol. Reprod. Dev. 2005; 72: 354-361Crossref PubMed Scopus (0) Google Scholar, Motosugi et al., 2005Motosugi N. Bauer T. Polanski Z. Solter D. Hiiragi T. Polarity of the mouse embryo is established at blastocyst and is not prepatterned.Genes Dev. 2005; 19: 1081-1092Crossref PubMed Scopus (143) Google Scholar, Hiiragi and Solter, 2004Hiiragi T. Solter D. First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing pronuclei.Nature. 2004; 430: 360-364Crossref PubMed Scopus (121) Google Scholar). Indeed, initial studies revealed no differences between early blastomeres in gene expression; however, these studies were restricted to the analysis of selected candidate genes (Wicklow et al., 2014Wicklow E. Blij S. Frum T. Hirate Y. Lang R.A. Sasaki H. Ralston A. HIPPO pathway members restrict SOX2 to the inner cell mass where it promotes ICM fates in the mouse blastocyst.PLoS Genet. 2014; 10: e1004618Crossref PubMed Scopus (82) Google Scholar, Guo et al., 2010Guo G. Huss M. Tong G.Q. Wang C. Li Sun L. Clarke N.D. Robson P. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst.Dev. Cell. 2010; 18: 675-685Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar, Ralston and Rossant, 2008Ralston A. Rossant J. Cdx2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo.Dev. Biol. 2008; 313: 614-629Crossref PubMed Scopus (237) Google Scholar, Dietrich and Hiiragi, 2007Dietrich J.E. Hiiragi T. Stochastic patterning in the mouse pre-implantation embryo.Development. 2007; 134: 4219-4231Crossref PubMed Scopus (352) Google Scholar). Furthermore, although blastomeres can retain the capacity to differentiate into either inner cell mass (ICM) or trophectoderm until at least the 16-cell stage (Suwinska et al., 2008Suwinska A. Czolowska R. Ozdzenski W. Tarkowski A.K. Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: expression of Cdx2 and Oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos.Dev. Biol. 2008; 322: 133-144Crossref PubMed Scopus (0) Google Scholar, Ziomek et al., 1982Ziomek C.A. Johnson M.H. Handyside A.H. The developmental potential of mouse 16-cell blastomeres.J. Exp. Zool. 1982; 221: 345-355Crossref PubMed Google Scholar, Rossant and Vijh, 1980Rossant J. Vijh K.M. Ability of outside cells from preimplantation mouse embryos to form inner cell mass derivatives.Dev. Biol. 1980; 76: 475-482Crossref PubMed Scopus (77) Google Scholar, Tarkowski and Wroblewska, 1967Tarkowski A.K. Wroblewska J. Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage.J. Embryol. Exp. Morphol. 1967; 18: 155-180PubMed Google Scholar), mounting evidence suggests that heterogeneities that bias cells toward one fate or the other may arise earlier. Lineage tracing studies revealed a cell fate bias in some blastomeres at the four-cell stage suggesting that early blastomeres may not contribute equally to all lineages (Tabansky et al., 2013Tabansky I. Lenarcic A. Draft R.W. Loulier K. Keskin D.B. Rosains J. Rivera-Feliciano J. Lichtman J.W. Livet J. Stern J.N. et al.Developmental bias in cleavage-stage mouse blastomeres.Curr. Biol. 2013; 23: 21-31Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, Piotrowska-Nitsche et al., 2005Piotrowska-Nitsche K. Perea-Gomez A. Haraguchi S. Zernicka-Goetz M. Four-cell stage mouse blastomeres have different developmental properties.Development. 2005; 132: 479-490Crossref PubMed Scopus (176) Google Scholar, Fujimori et al., 2003Fujimori T. Kurotaki Y. Miyazaki J. Nabeshima Y. Analysis of cell lineage in two- and four-cell mouse embryos.Development. 2003; 130: 5113-5122Crossref PubMed Scopus (104) Google Scholar), although this effect may not be conserved among all mouse strains (Alarcon and Marikawa, 2005Alarcon V.B. Marikawa Y. Unbiased contribution of the first two blastomeres to mouse blastocyst development.Mol. Reprod. Dev. 2005; 72: 354-361Crossref PubMed Scopus (0) Google Scholar). Analysis of epigenetic modifications at the four-cell stage has revealed an asymmetry between blastomeres in the levels of dimethylation of histone H3 at arginines 17 and 26 (H3R17 and H3R26) and in the levels of the chromatin modifiers Carm1 (Torres-Padilla et al., 2007Torres-Padilla M.E. Parfitt D.E. Kouzarides T. Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo.Nature. 2007; 445: 214-218Crossref PubMed Scopus (404) Google Scholar) and PRDM14 (Burton et al., 2013Burton A. Muller J. Tu S. Padilla-Longoria P. Guccione E. Torres-Padilla M.E. Single-cell profiling of epigenetic modifiers identifies PRDM14 as an inducer of cell fate in the mammalian embryo.Cell Rep. 2013; 5: 687-701Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). The levels of H3 methylation are proposed to influence cell fate determination, as those four-cell blastomeres displaying higher levels of methylation at H3R17 and H3R26 tend to contribute more progeny to the ICM of the embryo (Figure 2) (Burton et al., 2013Burton A. Muller J. Tu S. Padilla-Longoria P. Guccione E. Torres-Padilla M.E. Single-cell profiling of epigenetic modifiers identifies PRDM14 as an inducer of cell fate in the mammalian embryo.Cell Rep. 2013; 5: 687-701Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, Torres-Padilla et al., 2007Torres-Padilla M.E. Parfitt D.E. Kouzarides T. Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo.Nature. 2007; 445: 214-218Crossref PubMed Scopus (404) Google Scholar). Overexpression of CARM1 leads to increased H3R26 methylation and was associated with elevated expression of the ICM fate markers Nanog and Sox2 and positioning of progeny within the ICM (Torres-Padilla et al., 2007Torres-Padilla M.E. Parfitt D.E. Kouzarides T. Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo.Nature. 2007; 445: 214-218Crossref PubMed Scopus (404) Google Scholar). Recently, the development of photoactivatable fluorescence correlation spectroscopy (paFCS) techniques has made it possible to probe transcription factor dynamics in vivo (Zhao et al., 2017Zhao Z.W. White M.D. Alvarez Y.D. Zenker J. Bissiere S. Plachta N. Quantifying transcription factor-DNA binding in single cells in vivo with photoactivatable fluorescence correlation spectroscopy.Nat. Protoc. 2017; 12: 1458-1471Crossref PubMed Scopus (0) Google Scholar, Kaur et al., 2013Kaur G. Costa M.W. Nefzger C.M. Silva J. Fierro-Gonzalez J.C. Polo J.M. Bell T.D. Plachta N. Probing transcription factor diffusion dynamics in the living mammalian embryo with photoactivatable fluorescence correlation spectroscopy.Nat. Commun. 2013; 4: 1637Crossref PubMed Scopus (50) Google Scholar, Plachta et al., 2011Plachta N. Bollenbach T. Pease S. Fraser S.E. Pantazis P. Oct4 kinetics predict cell lineage patterning in the early mammalian embryo.Nat. Cell Biol. 2011; 13: 117-123Crossref PubMed Scopus (158) Google Scholar). Application of paFCS within the embryo revealed that the increases in Carm1-mediated histone H3 methylation promote DNA binding of Sox2, a transcription factor important for maintaining pluripotency, likely by increasing the accessibility of Sox2 binding sites (White et al., 2016aWhite M.D. Angiolini J.F. Alvarez Y.D. Kaur G. Zhao Z.W. Mocskos E. Bruno L. Bissiere S. Levi V. Plachta N. Long-lived binding of Sox2 to DNA predicts cell fate in the four-cell mouse embryo.Cell. 2016; 165: 75-87Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). This increased Sox2-DNA binding is thought to result in upregulation of Sox2-dependent genes linked to pluripotency (Goolam et al., 2016Goolam M. Scialdone A. Graham S.J. Macaulay I.C. Jedrusik A. Hupalowska A. Voet T. Marioni J.C. Zernicka-Goetz M. Heterogeneity in Oct4 and Sox2 targets biases cell fate in 4-cell mouse embryos.Cell. 2016; 165: 61-74Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, White et al., 2016aWhite M.D. Angiolini J.F. Alvarez Y.D. Kaur G. Zhao Z.W. Mocskos E. Bruno L. Bissiere S. Levi V. Plachta N. Long-lived binding of Sox2 to DNA predicts cell fate in the four-cell mouse embryo.Cell. 2016; 165: 75-87Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) biasing cells toward an embryonic fate. How the variability in histone H3 methylation arises de novo at the four-cell stage remains unclear, but it may originate from interplay between cell cleavage orientations (Zernicka-Goetz et al., 2009Zernicka-Goetz M. Morris S.A. Bruce A.W. Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo.Nat. Rev. Genet. 2009; 10: 467-477Crossref PubMed Scopus (198) Google Scholar), differences in gene expression (Shi et al., 2015Shi J. Chen Q. Li X. Zheng X. Zhang Y. Qiao J. Tang F. Tao Y. Zhou Q. Duan E. Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq.Development. 2015; 142: 3468-3477Crossref PubMed Google Scholar, Biase et al., 2014Biase F.H. Cao X. Zhong S. Cell fate inclination within 2-cell and 4-cell mouse embryos revealed by single-cell RNA sequencing.Genome Res. 2014; 24: 1787-1796Crossref PubMed Scopus (88) Google Scholar, Piras et al., 2014Piras V. Tomita M. Selvarajoo K. Transcriptome-wide variability in single embryonic development cells.Sci. Rep. 2014; 4: 7137Crossref PubMed Scopus (41) Google Scholar) resulting from noise-excitable mechanisms (Eldar and Elowitz, 2010Eldar A. Elowitz M.B. Functional roles for noise in genetic circuits.Nature. 2010; 467: 167-173Crossref PubMed Scopus (857) Google Scholar), or the possible asymmetric distribution of unidentified factors. The transition from oocyte to embryo occurs prior to zygotic genome activation and proceeds without RNA transcription. In fact, early development relies almost entirely on maternally provided factors deposited in the egg, many of which execute functions involved in protein transport, protein localization, and cell cycle (Gao et al., 2017Gao Y. Liu X. Tang B. Li C. Kou Z. Li L. Liu W. Wu Y. Kou X. Li J. et al.Protein expression landscape of mouse embryos during pre-implantation development.Cell Rep. 2017; 21: 3957-3969Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, Zhou and Dean, 2015Zhou L.Q. Dean J. Reprogramming the genome to totipotency in mouse embryos.Trends Cell Biol. 2015; 25: 82-91Abstract Full Text Full Text PDF PubMed Google Scholar). These factors may be unevenly distributed into each daughter cell during division in a process known as a partitioning error (Shi et al., 2015Shi J. Chen Q. Li X. Zheng X. Zhang Y. Qiao J. Tang F. Tao Y. Zhou Q. Duan E. Dynamic transcriptional symmetry-breaking in pre-implantation mammalian embryo development revealed by single-cell RNA-seq.Development. 2015; 142: 3468-3477Crossref PubMed Google Scholar, Huh and Paulsson, 2011Huh D. Paulsson J. Random partitioning of molecules at cell division.Proc. Natl. Acad. Sci. USA. 2011; 108: 15004-15009Crossref PubMed Scopus (101) Google Scholar). In the absence of transcription, partitioning errors likely account for the initial introduction of variability between cells. One such variably distributed factor may relate to mitochondrial rRNAs, which have recently been shown to become progressively heterogeneous by the end of the two-cell stage (Zheng et al., 2016Zheng Z. Li H. Zhang Q. Yang L. Qi H. Unequal distribution of 16S mtrRNA at the 2-cell stage regulates cell lineage allocations in mouse embryos.Reproduction. 2016; 151: 351-367Crossref PubMed Scopus (3) Google Scholar). Whether and how this might influence or translate into asymmetries arising at the four-cell stage remains to be determined. Minor activation of zygotic transcription is first detected at the late one-cell stage with higher activity in the male pronucleus than the female pronucleus (Zhou and Dean, 2015Zhou L.Q. Dean J. Reprogramming the genome to totipotency in mouse embryos.Trends Cell Biol. 2015; 25: 82-91Abstract Full Text Full Text PDF PubMed Google Scholar). However, the majority of zygotic genome activation first occurs at the two-cell stage and contributes to the preparation of basic cellular machinery involved in functions such as protein translation, cell metabolism, and RNA processing (Gao et al., 2017Gao Y. Liu X. Tang B. Li C. Kou Z. Li L. Liu W. Wu Y. Kou X. Li J. et al.Protein expression landscape of mouse embryos during pre-implantation development.Cell Rep. 2017; 21: 3957-3969Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). From this point on, the newly synthesized embryonic products gradually replace the maternally supplied factors and become the main regulators of development. The first major morphological changes in the embryo begin with the onset of polarization and compaction at the eight-cell stage. Until the early eight-cell stage, each cell within the embryo is morphologically similar. Within 1–3 hr of reaching the eight-cell stage, blastomeres begin to display the first outward signs of radial polarity with the establishment of distinct apical and basolateral domains (Figure 2) (Ziomek and Johnson, 1980Ziomek C.A. Johnson M.H. Cell surface interaction induces polarization of mouse 8-cell blastomeres at compaction.Cell. 1980; 21: 935-942Abstract Full Text PDF PubMed Google Scholar). During this time, the actin cytoskeleton is reorganized to form an apical pole rich in microvilli and there is a polarized redistribution of cytoplasmic organelles and cytoskeletal elements (Ducibella et al., 1977Ducibella T. Ukena T. Karnovsky M. Anderson E. Changes in cell surface and cortical cytoplasmic organization during early embryogenesis in the preimplantation mouse embryo.J. Cell Biol. 1977; 74: 153-167Crossref PubMed Google Scholar). The contact-free surface of each blastomere forms the apical domain, characterized by clustering of the microvilli and the prog" @default.
• W2807811455 created "2018-06-21" @default.
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• W2807811455 date "2018-06-01" @default.
• W2807811455 modified "2023-10-11" @default.
• W2807811455 title "Instructions for Assembling the Early Mammalian Embryo" @default.
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